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Systemic sclerosis (SSc) is a generalized disease of the connective tissue, arterioles, and microvessels, characterized by the appearance of fibrosis and vascular obliteration. There are two main phenotypical forms of SSc: a diffuse cutaneous form that extends towards the proximal region of the limbs and/or torso, and a limited cutaneous form where the cutaneous sclerosis only affects the extremities of the limbs (without passing beyond the elbows and knees). There also exists in less than 10% of cases forms that never involve the skin. This is called SSc sine scleroderma. The prognosis depends essentially on the occurrence of visceral damage and more particularly interstitial lung disease (which is sometimes severe), pulmonary arterial hypertension, or primary cardiac damage, which represent the three commonest causes of mortality in SSc. Another type of involvement with poor prognosis, scleroderma renal crisis, is rare (less than 5% of cases). Cutaneous extension is also an important parameter, with the diffuse cutaneous forms having less favorable prognosis., (© 2021. The Author(s).)

Objectives: To determine the causes of death and risk factors in systemic sclerosis (SSc)., Methods: Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation., Results: We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile., Conclusion: Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival., Competing Interests: Competing interests: OD reports personal fees from 4D Science, grants and personal fees from Actelion, personal fees from Active Biotech, grants and personal fees from Bayer, personal fees from Biogen Idec, personal fees from BMS, grants and personal fees from Boehringer Ingelheim, personal fees from ChemomAb, personal fees from EpiPharm, personal fees from EspeRare Foundation, personal fees from Genentech/Roche, personal fees from GSK, personal fees from Inventiva, personal fees from Lilly, personal fees from Medac, personal fees from Mepha, personal fees from MedImmune, personal fees from Pharmacyclics, grants and personal fees from Pfizer, grants and personal fees from Sanofi, personal fees from Serodapharm, personal fees from Sinoxa, personal fees from AbbVie, personal fees from iQone Healthcare, outside the submitted work. In addition, OD has a patent mir-29 for the treatment of systemic sclerosis licensed. FI reports personal fees from AbbVie, personal fees from BMS, personal fees from MSD, personal fees from Novartis, outside the submitted work. JHWD reports personal fees from Actelion, grants and personal fees from Anamar, grants and personal fees from Bayer Pharma, grants and personal fees from Boehringer Ingelheim, grants from Celgene, personal fees from Galapagos, grants from GSK, grants and personal fees from Inventiva, personal fees from Pfizer, grants and personal fees from UCB, grants from Novartis, other from 4D Science, outside the submitted work. JvL reports personal fees from Pfizer, grants and personal fees from MSD, personal fees from Eli Lilly, personal fees from BMS, personal fees from Roche, outside the submitted work. Other coauthors have nothing to disclose., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cardiac involvement contributes to the severity of SSc and should carefully be investigated and managed in SSc patients. Although it is commonly sub-clinical, once symptomatic it has a poor prognosis. Several complementary tools (circulating biomarkers, electrocardiography, echocardiography, scintigraphy or MRI) allow the assessment of all the various cardiac structures (endocardium, myocardium and pericardium) and heart function. Treatment remains empirical but cardiac trials in SSc can add data to the treatment of this complication., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc., Methods and Results: This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results., Conclusion: NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Digital ulcers (DU) are a burden in systemic sclerosis (SSc). Microangiopathy is a cardinal feature of SSc that plays a critical role in the development of DU. However, whether injury of medium or large vessels also contributes to DU in SSc remains controversial., Methods: To measure concomitantly in SSc patients with and without active DU: (i) the Augmentation Index of the reflected wave (Aix&#95;75) by radial applanation tonometry, an index of small and medium arterial function; (II) the aortic pulse wave velocity (PWV), a marker of large vessel injury (aortic stiffness)., Results: Sixty-three consecutive SSc patients were included (49 females, aged 60 [49-65] years, disease duration of 8.5 [5-13] years), including 10 (15.9%) with active DU. Patients with active DU versus those without had increased Aix&#95;75 (35% [28-38] versus 28% [20-34], P=0.041) whereas no difference existed in PWV (7.0m/s [6.7-10.1] versus 7.6m/s [6.8-8.7], P=0.887), in systolic, diastolic, as well as aortic pulse pressure (P=0.126, 0.592, and 0.161, respectively). When compared to patients in the low tertile, patients having Aix&#95;75 in the highest tertile had 10-fold more DU (OR=10.23; 95% CI 1.12 to 93.34, P=0.039)., Conclusion: The presence of DU is associated with increased Aix&#95;75 whereas there is no relation with PWV. These data suggest that small and medium arteries are involved in the occurrence of DU whether large vessel stiffness does not contribute. Whether Aix&#95;75 is predictive of further DU remained to be studied., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: Heart involvement in systemic sclerosis (SSc) is a strong prognostic factor. Our aim was to examine left ventricle (LV) and right ventricle (RV) involvement., Methods: We examined LV and RV, systolic and diastolic functions, using echocardiography and Tissue-Doppler echocardiography (TDE) indexes, in a cohort of 212 consecutive SSc patients seen during a 9-month period at 2 institutions (Paris, France and Los Angeles, USA). They were compared to 50 healthy controls., Results: When compared to controls, SSc patients had consistently impaired RV indices that include reduced RV contractility (p < 0.001), larger right atrial area (p = 0.027) and overall RV diastolic dysfunction (25% of SSc patients versus 0% of controls; p < 0.001). Patients also exhibited alterations in LV contractility and diastolic function (p < 0.001 each). In multivariate analysis, RV contractility as expressed by the TDE S(T) parameter was associated with TDE LV contractility S(M) (p = 0.030), DLCO (p = 0.013) whereas RV diastolic impairment was associated with systolic pulmonary artery pressure (p = 0.015). A subgroup of 27 patients had proven pulmonary arterial hypertension (PAH); comparison between SSc-PAH versus SSc free of PAH patients revealed reduced LV diastolic function (transmitral E/A ratio, p = 0.045 and E(A) < 10 cm/s, p = 0.029), reduced overall RV contractility (21.5% versus 4.5%; p = 0.03) and reduced RV diastolic function (transtricuspid E/A ratio; p = 0.014 and 68% versus 29% with impaired function; p = 0.001)., Conclusions: Our data show that RV is commonly affected in SSc with predominant impaired diastolic function. Several factors, including primary heart, lung vascular disease and pulmonary hypertension, contribute to such impairment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc)., Methods: Angiotensin II Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) autoantibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup., Results: Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19-6.84 and HR 3.39, 95% CI 1.35-8.50, respectively). A first multivariate Cox analysis including functional autoantibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22-8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoantibodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75-52.64) together with the presence at baseline of active DU or history of DU., Conclusion: Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoantibodies may allow for earlier management and therapeutic intervention.

Objective: To measure plasma concentrations of high-sensitivity cardiac troponin T (HS-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with systemic sclerosis (SSc; scleroderma) and age- and sex-matched healthy control subjects, and to examine the contribution of traditional cardiovascular risk factors and SSc features to the concentrations of these 2 cardiac biomarkers., Methods: Plasma HS-cTnT and NT-proBNP concentrations were measured using the electrochemiluminescence method and sandwich immunoassay, respectively., Results: The study group comprised 161 unrelated patients with SSc and 213 matched control subjects. HS-cTnT and NT-proBNP plasma levels were significantly increased in SSc patients compared with controls (both P < 0.001). Similar results were observed in the subgroup of patients with SSc who had no cardiovascular risk factors (n = 72). Multivariate logistic regression analysis confirmed diabetes mellitus (P = 0.006), high blood pressure (P = 0.021), precapillary pulmonary hypertension (P = 0.039), and the diffuse cutaneous SSc (P = 0.004) as factors independently associated with an HS-cTnT level of >14 ng/liter. Increased NT-proBNP concentrations were associated only with the presence of precapillary pulmonary hypertension (P < 0.001). Normal concentrations of both HS-cTnT and NT-proBNP had a high negative predictive value for precapillary pulmonary hypertension (92%), and the combination of increased values of these 2 markers had the highest strength of association with precapillary pulmonary hypertension in logistic regression analysis., Conclusion: HS-cTnT and NT-proBNP concentrations are increased in patients with SSc, even in those who are free of cardiovascular risk factors. These easily obtained biomarkers may be useful for systematic evaluation and stratification of SSc patients, especially to identify those at risk of pulmonary hypertension., (© 2015 American College of Rheumatology.)

Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e., related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other populations., (© The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate routinely collected non-invasive tests from 2 systemic sclerosis (SSc) cohorts to determine their predictive value alone and in combination versus right heart catheterization (RHC)-confirmed pulmonary arterial hypertension (PAH)., Methods: We evaluated 2 cohorts of patients who were at risk or with incident PAH: (1) The Pulmonary Hypertension Assessment and Recognition Outcomes in Scleroderma (PHAROS) cohort and (2) an inception SSc cohort at Cochin Hospital, Paris, France. Estimated right ventricular systolic pressure (eRVSP) as determined by transthoracic echocardiogram (TTE) and pulmonary function test (PFT) measures was evaluated, and the predictive values determined. We then evaluated patients with PAH missed on TTE cutoffs that were subsequently identified by a PFT measure., Results: In the PHAROS cohort (n = 206), 59 (29%) had RHC-defined PAH. An eRVSP threshold of 35-50 mm Hg failed to diagnose PAH in 7% to 31% of patients, 50% to 70% of which (n = 2-13) were captured by PFT measures. In the Cochin cohort (n = 141), 10 (7%) patients had RHC confirmed PAH. An eRVSP threshold of 35-50 mm Hg missed 0% to 70% (n = 0-7) of patients, of which 0% to 68% (n = 0-6) were met by PFT measures. The combination of TTE and PFT improved the negative predictive value for diagnosing PAH., Conclusion: In 2 large SSc cohorts, screening with TTE and PFT captured a majority of patients with PAH. TTE and PFT complement each other for the diagnosis of PAH.

Objective: SSc is known as the most severe connective tissue disorder, and to be associated with a high mortality risk. Some improvements in therapy for SSc have been achieved in recent years and some preliminary data have suggested an improvement in patient survival. Thus, we set out to determine whether mortality rate in SSc patients has decreased over the past 40 years through a meta-analysis of cohort studies., Methods: We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to June 2010. All cohort studies reporting on SSc mortality were analysed. We then calculated pooled standardized mortality ratios (SMRs) of SSc mortality and calculated their changes over time using meta-regression analysis., Results: Nine studies were included, corresponding to a total of 2691 SSc patients. The pooled SMR was 3.53 [95% CI 3.03, 4.11, P < 0.0001; I(2 )= 93%, P(het) = 0.001]. Mid-cohort year ranged from 1977 to 1995 (before 1980: two studies; 1980-90: five studies; and after 1990: two studies): adjusted meta-regression analysis did not show significant change in SMR over time (P = 0.523). Among 732 deaths, heart involvement was the most frequent cause of deaths (29%) followed by lung involvement., Conclusion: Our results confirm that SSc is a devastating condition as reflected by a pooled SMR of 3.5. Additionally, SMR has not significantly changed over the past 40 years. Further studies are needed to assess the effect of the most recent available therapies on mortality in SSc.

Objective: To evaluate the possible merit of endothelial markers for the prediction of ischaemic digital ulcers in patients with systemic sclerosis (SSc)., Methods: Circulating endothelial progenitor cells (EPC), circulating endothelial cells and serum levels of placental growth factor (PlGF), soluble vascular adhesion molecule and vascular endothelial growth factor were measured in a prospective cohort of 100 SSc patients. The primary outcome was the occurrence of one or more new ischaemic digital ulcers during a planned 3-year follow-up., Results: After the follow-up period, 17 patients developed new digital ulcers. By multivariate analysis focused on biomarkers, high PlGF serum levels and low EPC counts were identified as predictors of the occurrence of at least one new digital ulcer. In a secondary model including biomarkers together with clinical SSc characteristics all predictors of digital ulcers defined by p≤0.1 in univariate analysis, high PlGF serum levels (HR 7.26, 95% CI 1.92 to 27.41) and a history of digital ulcers (HR 9.32, 95% CI 1.51 to 59.83) were identified as independent predictors of a new digital ulcer. In an alternative model excluding patients with a history of digital ulcers at baseline, high PlGF serum levels (HR 13.46, 95% CI 1.58 to 114.73) and low EPC counts (HR 7.95, 95% CI 2.09 to 30.09) remained predictive of new digital ulcer occurrence during follow-up., Conclusion: This study identified high PlGF serum levels and low circulating EPC counts as predictors of new digital ulcers in SSc. It highlights the critical role of angiogenesis in this vascular outcome. These markers may improve digital ulcer risk stratification and therefore allow earlier therapeutic intervention.

Objective: To develop a score to estimate the risk of developing pulmonary hypertension (PH) in patients with systemic sclerosis (SSc)., Methods: We first examined the prevalence and characteristics of precapillary PH confirmed by right-heart catheterization in a cross-sectional (derivation) sample of 1,165 SSc patients, and we developed a risk prediction score (RPS) based on simple clinical observations associated with PH. We next prospectively tested the 3-year predictive power of the "Cochin RPS" in a separate (validation) sample of 443 patients presenting with PH-free SSc at baseline., Results: In the derivation sample, age, forced vital capacity, and diffusing capacity for carbon monoxide/alveolar volume were independently associated with the presence of PH and were used to create the Cochin RPS. PH developed during followup in 20 patients in the validation sample. The area under the receiver operating characteristic curve of the Cochin RPS was 0.87 (95% confidence interval 0.79-0.95). With a cutoff value of 2.73, patients at risk of PH during followup could be identified with 89.5% sensitivity and 74.1% specificity. PH occurred in 0.6% of patients in the lowest 2 quintiles of the Cochin RPS, in 1.7% of patients in the third and fourth quintiles, and in 17.1% of patients in the highest quintile (P<0.0001 by log rank test). Patients in the highest quintile incurred a >35-fold higher risk of developing PH compared with patients in the 2 lowest quintiles (P=0.001)., Conclusion: Using routine clinical observations, we developed a simple score that accurately predicted the risk of PH in SSc., (Copyright © 2011 by the American College of Rheumatology.)

Objective: To measure the prevalence of different types of pulmonary hypertension (PH) and to identify patients with systemic sclerosis (SSc) at highest risk in a multicenter European sample, with a metaanalysis of relevant studies., Methods: Consecutive patients with SSc recruited at 11 French and Italian centers underwent detailed evaluations, including Doppler echocardiography, chest computed tomography, pulmonary function tests, and right-heart catheterization (RHC), to detect the presence and causes of PH. A metaanalysis was performed, including data from 4 other studies., Results: Among 206 patients in whom it was suspected, PH was confirmed by RHC in 83 patients (7%). Precapillary PH was found in 64 patients (5%), of whom 42 had pulmonary arterial hypertension (PAH) and 22 had PH secondary to interstitial lung disease (ILD). RHC identified 17 patients (1%) with postcapillary PH secondary to left-heart disease. Patients with DLCO/alveolar volume < 70% were more likely to have precapillary PH (87.5% vs 42%; p < 0.0001). Precapillary and postcapillary PH were associated with advanced age (68 ± 14 vs 59 ± 12 yrs, p < 0.0001, and 74 ± 16 vs 61.5 ± 10 yrs, p < 0.0001, respectively). The metaanalysis of 3818 patients showed a prevalence of precapillary PH of 9% (95% CI 6%-12%) and identified advanced age, longer disease duration, and limited cutaneous disease subset as risk factors for this condition., Conclusion: The prevalence of precapillary PH in our multicenter study of SSc was 5%, and in the metaanalysis 9%. Our observations support use of RHC to confirm the presence of precapillary PH suspected by noninvasive testing. We also identified patients at high risk who should be carefully monitored.

Systemic sclerosis (SSc) is a connective tissue disease characterised by widespread vascular lesions and fibrosis of the skin and internal organs. Cardiac involvement is recognised as a poor prognostic factor when clinically evident. Primary myocardial involvement is common in SSc. Increasing evidence strongly suggests that myocardial involvement is related to repeated focal ischaemia leading to myocardial fibrosis with irreversible lesions. Reproducible data have shown that this relates to microcirculation impairment with abnormal vasoreactivity, with or without associated structural vascular abnormalities. Consistently, atherosclerosis and macrovascular coronary lesions do not seem to be increased in SSc. Myocardial involvement leads to abnormal systolic and diastolic left ventricular dysfunction and right ventricular dysfunction. Sensitive and quantitative methods have demonstrated the ability of vasodilators, including calcium channel blockers and angiotensin converting enzyme inhibitors, to improve both perfusion and function abnormalities further emphasising the critical role of microcirculation impairment. Recent quantitative methods such as tissue Doppler echocardiography and magnetic resonance imaging have underlined these results.

Objectives: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc)., Methods: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression., Results: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction., Conclusion: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective.

Heart involvement, including primary myocardial involvement, is very common in systemic sclerosis. There is strong evidence that primary myocardial involvement is related to repeat focal ischaemic injury causing subsequent irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor; thus preclinical identification is highly encouraged. The severity of heart involvement has been confirmed recently. Echocardiography, including pulsed tissue Doppler echocardiography, is the cornerstone of routine heart assessment. Myocardial perfusion may be assessed by single photon emission computed tomography. If available, cardiac magnetic resonance imaging should be considered as it allows simultaneous measurement of ventricular volumes and function and myocardial perfusion, and assessment of possible inflammation and/or fibrosis. Biological variables, such as B-type natriuretic peptides, are highly relevant, valuable markers of global heart involvement in systemic sclerosis and should be considered for screening of patients and/or research purposes., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Background: Cardiac involvement, a common and often fatal complication of systemic sclerosis (SSc), is currently detected by standard echocardiography enhanced by tissue Doppler echocardiography (TDE)., Objective: The performance of the biomarker of cardiovascular disease, N-terminal pro-brain natriuretic peptide (NT-proBNP), in the detection of cardiac involvement by SSc was examined., Methods: A total of 69 consecutive patients with SSc (mean (SD) age 56 (13) years, 56 women) were prospectively studied with standard echocardiography and TDE measurements of longitudinal mitral and tricuspid annular velocities. Plasma NT-proBNP was measured in all patients., Results: Overall, 18 patients had manifestations of cardiac involvement, of whom 7 had depressed left ventricular and 8 depressed right ventricular myocardial contractility, and 8 had elevated systolic pulmonary arterial pressure. Patients with reduced contractility had increased mean (SD) NT-proBNP (704 (878) pg/ml versus 118 (112) pg/ml in patients with normal myocardial contractility, p<0.001). Similarly, NT-proBNP was higher in patients with (607 (758) pg/ml) than in patients without (96 (78) pg/ml) manifestations of overall cardiac involvement (p<0.001). Receiver operating characteristic analysis showed NT-proBNP reliably detected depressed myocardial contractility and overall cardiac involvement (area under the curve 0.905 (95% CI 0.814 to 0.996) and 0.935 (95% CI 0.871 to 0.996), respectively). Considering patients with SSc with normal echocardiography and TDE as controls, and using a 125 pg/ml cut-off concentration, sensitivity and specificity were 92% and 71% in the detection of depressed myocardial contractility, and 94% and 78% for overall cardiac involvement., Conclusions: NT-proBNP reliably detected the presence of cardiac involvement and appears to be a very useful marker to risk stratify patients presenting with SSc.

Objective: The 6-minute walk test (6MWT) is an important prognostic tool in various cardiovascular diseases and has been considered as a surrogate endpoint. However, conflicting results have been reported in systemic sclerosis (SSc). Our objective was to evaluate the relationships of the 6-min walking distance (6MWD) and organ damage in SSc., Methods: Eighty-seven consecutive patients with SSc were included and prospectively investigated; they underwent 6MWT in addition to conventional assessment of possible lung, heart, kidney, skin, and muscle involvement, and disease activity scoring, severity, and quality of life determination., Results: Twenty-six patients (30%) had an abnormal 6MWT and the mean 6MWD was 461.8 +/- 103.0 m. When considering 6MWT as a binary variable - normal or abnormal - C-reactive protein (CRP) was the only independent variable associated with abnormal 6MWT. Considered as a continuous variable, the 6MWD was associated with measures of lung involvement and inflammation, with the activity and severity of disease, and also with quality of life; nevertheless, calcinosis was the only independent factor associated in multivariate analyses with a trend for an association for CRP., Conclusion: The 6MWD relates to broad factors in SSc and these results raise doubts about the specificity of the 6MWD in this systemic disease, and its relevance to monitoring therapy.

Heart involvement, including primary myocardial involvement, is very common in systemic sclerosis (SSc). When clinically evident, cardiac involvement is recognized to be a very poor prognostic factor. Thus pre-clinical identification is highly encouraged. Echocardiography, including pulsed tissue Doppler echocardiography, is the cornerstone of routine heart assessment as it allows the detection of reduced systolic/ diastolic function, as well as the measurement of pulmonary artery pressure, and the possible detection of valvular or pericardial involvement. Myocardial perfusion may be also assessed by single photon emission computed tomography, and if available, by cardiac magnetic resonance imaging. Since the introduction of routine assay for natriuretic peptides, and their initial application for the diagnosis of acute heart failure, B-type natriuretic peptide assays are now recommended for a wide number of applications and have been introduced as a major tool, in particular in primary care, in worldwide guidelines. Within the context of SSc, recent studies have demonstrated that BNP and NT-proBNP are highly relevant for the diagnosis and the prediction of pulmonary hypertension occurrence. Moreover, NT-proBNP allows the detection of both reduced left ventricular/right ventricular contractility, or pulmonary hypertension, suggesting its potential role as a first line tool in primary care setting for the overall cardiac assessment of SSc in which cardiovascular complications are a burden.

Purpose of Review: Primary myocardial involvement is common in systemic sclerosis. There is strong evidence that this involvement is related to repeat focal ischemic injury causing irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor; thus preclinical identification is highly encouraged., Recent Findings: The severity of heart involvement has been confirmed and patients having systemic sclerosis with antitopoisomerase I antibodies seem to be at higher risk. Echocardiography, coupled, if possible, to pulsed tissue Doppler, is the cornerstone of heart assessment. Myocardial perfusion may be assessed by single photon emission computed tomography. When available, cardiac magnetic resonance imaging should be considered as it allows simultaneous measurement of volumes and ventricular function, myocardial perfusion, and assessment of possible inflammation and/or fibrosis., Summary: As a result of recent innovations, clinicians have a large panel of methods - some of these possibly reserved for research--whereas the others seem to be widely available and suitable for routine clinical practice. Indeed, conventional echocardiography, pulsed tissue Doppler, and natriuretic peptides may be used for routine assessment.

Primary myocardial involvement is common in SSc. Increasing evidence strongly suggests that this involvement is related to repeat focal ischaemic injury causing irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor, thus pre-clinical identification is highly encouraged. Echocardiography, if possible coupled to pulsed tissue Doppler, is the cornerstone of heart assessment even if radionuclide ventriculography remains the gold standard for evaluation of ventricular function. Myocardial perfusion may be assessed by single photon emission CT, but cardiac MRI will probably supplant this technique; it, furthermore, offers the possibility to concomitantly determine, ventricular function, myocardial perfusion and tissular parameters (i.e. myocarditis or burden of fibrosis). Conduction system abnormalities are common but not serious, while arrhythmias may be life-threatening, necessitating 24-h ambulatory Holter ECG. Natriuretic peptides have been used mainly when the heart has been involved secondary to pulmonary arterial hypertension, but may also be useful for the identification of early heart dysfunction. Their predictive value should also be investigated when there is primary heart involvement.

Objective: To assess the prevalence of primary cardiac complications in a large population of patients with systemic sclerosis (SSc), using recently developed echocardiographic techniques., Methods: We prospectively studied 100 consecutive patients (mean +/- SD age 54 +/- 14 years; 86 women) presenting with SSc without pulmonary arterial hypertension or clinical manifestations of heart failure. All patients underwent standard echocardiography, along with measurements of longitudinal velocities by tissue Doppler imaging (TDI) to assess left ventricular (LV) and right ventricular (RV) contractility and LV diastolic function. Results were compared with those in 26 age- and sex-matched healthy controls., Results: Patients with SSc had a wider mean left atrial diameter and impaired relaxation compared with the controls. A trend was observed toward a smaller LV ejection fraction (EF) in the patients (mean +/- SD 64.9 +/- 0.6%) than in the controls (67.2 +/- 0.7%), as well as higher pulmonary artery pressure (mean +/- SD 33.3 +/- 0.6 mm Hg versus 30.8 +/- 1.0 mm Hg). LVEF was <55% in 7 patients versus none of the controls. Peak systolic mitral annular velocity as measured by TDI was <7.5 cm/second in 14 patients versus none of the controls (P = 0.040). Mitral annulus early diastolic velocity was <10 cm/second in 30 patients versus 2 of the controls (P = 0.022). Fifteen patients and none of the controls had reduced peak systolic tricuspid annular velocity (P = 0.039). The TDI results correlated with each other, but not with lung abnormalities or other disease characteristics., Conclusion: Depression of LV and RV systolic and LV diastolic function is common in patients with SSc and is due to primary myocardial involvement. Considering the major contributions of TDI, the addition of this simple technique to standard measurements may improve the detection of heart involvement in patients with SSc.

Objective: To evaluate predictors of pulmonary arterial hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc)., Methods: Routine clinical assessments as well as measurements of the diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA) ratio and N-terminal pro-brain natriuretic peptide (NT-proBNP) level were performed in a prospective cohort of 101 SSc patients who did not have PAH or severe comorbidities. After a planned 36-month followup, we evaluated the predictive value of these parameters for the development of precapillary PAH, as demonstrated by cardiac catheterization, disease progression, and death. Criteria for cardiac catheterization were a systolic pulmonary artery pressure (PAP) of >40 mm Hg on echocardiography, a DLCO value of <50% without pulmonary fibrosis, and unexplained dyspnea., Results: Eight patients developed PAH, 29 had disease progression, and 10 died during a median followup of 29 months. Kaplan-Meier analysis identified the following baseline parameters as being predictors of PAH: DLCO/VA ratio <70% or <60% (P<0.01 for each comparison), elevated plasma NT-proBNP level (>97th percentile of normal; P = 0.005), echocardiographically estimated systolic PAP >40 mm Hg (P=0.08), and erythrocyte sedimentation rate >28 mm/hour (P=0.015). In multivariate analyses, an elevated baseline NT-proBNP level (hazard ratio [HR] 9.97 [95% confidence interval (95% CI) 1.69-62.42]) and a DLCO/VA ratio <60% (HR 36.66 [95% CI 3.45-387.6]) were predictors of the occurrence of PAH during followup. An increased NT-proBNP level together with a decreased DLCO/VA ratio of <70% was highly predictive of the occurrence of PAH during followup (HR 47.20 [95% CI 4.90-450.33])., Conclusion: This prospective study identified a decreased DLCO/VA ratio and an increased NT-proBNP as predictors of PAH in SSc. Use of these markers should result in improved PAH risk stratification and allow earlier initiation of therapy.

Objective: To evaluate the short-term effects of bosentan on myocardial perfusion and function assessed by cardiac magnetic resonance imaging (MRI) and Tissue-Doppler echography (TDE) respectively in patients with systemic sclerosis (SSc)., Methods: We prospectively evaluated 18 SSc patients without clinical heart failure and with normal pulmonary arterial pressure. MRI perfusion index and systolic and diastolic strain rates (SR) determined by TDE were assessed at baseline for comparison with healthy controls (after a 72-hour vasodilator washout period), and repeated after 4 weeks of bosentan treatment (62.5 mg bid for 2 weeks titrated to 125 mg bid for 2 weeks)., Results: Patients with SSc had decreased MRI perfusion index and TDE SR in comparison with healthy controls. Bosentan treatment led to a significant increase in median (range) global MRI perfusion index [from 0.17 (0.09-0.23) at Day 0 to 0.22 (0.13-0.30) after bosentan treatment; p = 0.0004], systolic SR [from 2.1 (1.3-3.1) s-1 to 2.8 (2.1-4.8) s-1; p = 0.0002), and diastolic SR [from 2.6 (1.4-6.7) to 3.6 (2.0-7.6) s-1; p = 0.0003]., Conclusion: Short-term treatment with bosentan simultaneously improves myocardial perfusion and function, as evaluated by highly sensitive and quantitative methods, in patients with SSc. Whether additional remodeling effect may be observed after longterm treatment with bosentan remains to be determined.

Aims: Systemic sclerosis (SSc) is a connective tissue disorder characterized by frequent myocardial involvement. Alteration in left ventricular (LV) function is reported to be rare; however, it may be underestimated by conventional measurements. Our aim was to prospectively investigate LV function in SSc patients, using Tissue Doppler echocardiography (TDE), a modern and accurate method of assessing myocardial function., Methods and Results: Seventeen consecutive SSc patients with normal cardiac examination, pulmonary artery pressure (PAP) and radionuclide LV ejection fraction (EF) were prospectively investigated. Myocardial perfusion was investigated using single-photon-emission computerized tomography (SPECT). Echocardiography (ECHO), systolic and diastolic strain-rate (SR) measured in the posterior wall by TDE were used to investigate myocardial function, and compared with results of 15 matched controls. All patients (53+/-8 years; 14 women; systolic PAP 33+/-6 mmHg; LVEF 67+/-8%) had myocardial SPECT perfusion abnormalities. Despite normal ECHO, they had lower systolic SR than controls (1.7+/-0.5 versus 3.8+/-1.7 cm-1, p<0.0001), and lower diastolic SR (3.7+/-1.5 versus 5.6+/-1.2 cm-1, p=0.0004). Ten SSc patients had reduced systolic SR<1.7 cm-1 and 11 reduced diastolic SR<3.5 cm-1., Conclusion: Frequent abnormal myocardial perfusion is confirmed in SSc patients. Reduced contractility is also frequent as detected by TDE, despite normal radionuclide LVEF.

Background: Primary myocardial involvement due to microcirculation impairment is common in systemic sclerosis (SSc). Cardiovascular magnetic resonance imaging (MRI) and tissue Doppler echocardiography (TDE) were recently shown to be more sensitive than conventional methods for the respective assessment of myocardial perfusion and contractility. Previous studies have suggested that dihydropyridine-type calcium channel blockers mitigate both myocardial perfusion and function abnormalities., Objective: To investigate the effects of nifedipine on myocardial perfusion by MRI and on contractility by TDE, in patients with SSc., Patients and Methods: 18 patients with SSc without clinical heart failure and with normal pulmonary arterial pressure (14 women, 4 men; mean (SD) age 59 (9) years; mean (SD) disease duration 7 (4) years, 10 with diffuse and 8 with limited cutaneous forms) were prospectively evaluated. The MRI perfusion index, determined from time-intensity curves, and systolic and diastolic strain rate determined by TDE were assessed at baseline, after a 72 hour vasodilator washout period, and after 14 days of oral treatment with nifedipine 60 mg/day., Results: Nifedipine treatment led to a significant increase in the MRI perfusion index (mean (SD) 0.26 (0.07) v 0.19 (0.05) at baseline, p = 0.0003) and in systolic and diastolic strain rate (2.3 (0.6) v 1.5 (0.4) s(-1) at baseline, p = 0.0002, and 4.2 (1.6) v 3.0 (1.2) at baseline, p = 0.0003, respectively)., Conclusion: Fourteen days of treatment with nifedipine simultaneously improves myocardial perfusion and function, as evaluated by highly sensitive and quantitative methods.

Background: Increased expression of CD40L has been reported on activated CD4+ T lymphocytes in systemic sclerosis. CD40L can be expressed in soluble form (sCD40L)., Objective: To compare sCD40L concentrations in patients with systemic sclerosis and healthy controls., Methods: Quantitative sandwich ELISA was used to measure plasma sCD40L in systemic sclerosis (n = 50) and matched healthy controls (n = 20). Patients with systemic sclerosis had limited cutaneous disease (29), digital ulcers (14), pulmonary arterial hypertension (PAH) (10), pulmonary fibrosis on CT (23), positive anti-Scl70 (14), and anti-centromere antibodies (10). Calcium channel blockers were discontinued 72 hours before measurements., Results: Median (range) sCD40L concentration (pg/ml) was higher in systemic sclerosis than in controls (495 (10 to 7720) v 79 (50 to 118); p = 0.003), in limited cutaneous disease v diffuse disease (620 (20 to 7720) v 250 (10 to 2690); p = 0.005), in patients with digital ulcers v those without (1430 (36 to 7720) v 370 (10 to 2320); p = 0.002), and in those with PAH v those without (995 (15 to 3850) v 400 (10 to 7720); p = 0.048). sCD40L correlated with pulmonary arterial pressure estimated by Doppler echocardiography (r = 0.41; p = 0.005)., Conclusions: The soluble form of CD40L is increased in plasma in systemic sclerosis and may be associated with vascular complications of the disease.

Objective: To assess right ventricular (RV) function in patients with early systemic sclerosis (SSc) and the acute effects of calcium channel blockers on RV ejection fraction (RVEF)., Methods: Forty-two consecutive patients with SSc with less than 5 years' disease duration and normal pulmonary arterial pressure (35 women, 7 men; mean age 54.3 +/- 9.7 years; 16 with diffuse and 26 with limited cutaneous forms, systolic pulmonary arterial pressure 30.3 +/- 5.4 mmHg) were prospectively evaluated. All underwent pulmonary function testing, echocardiography, and radionuclide ventriculography at rest and 2 hours after receiving 40 mg oral nicardipine, and were compared at baseline with 20 gender and age matched controls., Results: None of the patients with SSc had clinical evidence of heart failure. At baseline, SSc patients had significantly lower LVEF (68.5% +/- 7.9 vs 72.4% +/- 5.0, p = 0.049) and RVEF (36.5% +/- 7.0 vs 45.8% +/- 5.7, p < 0.0001). Sixteen patients had reduced RVEF (< 35%), 3 had reduced LVEF (< 55%), and 10 had reduced peak filling rate (PFR). RVEF correlated to both LVEF and PFR (r = 0.64, p < 0.0001, and r = 0.36, p = 0.0037, respectively), whereas no correlation was found with pulmonary function impairment or pulmonary arterial pressure. Nicardipine resulted in a significant increase in RVEF (from 36.5% +/- 7.0 to 42.3% +/- 8.4, p < 0.001) whereas afterload indicated by mean arterial pressure did not differ significantly., Conclusion: Reduced RVEF appears to be a common feature in early SSc; it may be due to intrinsic myocardial involvement and is acutely improved by nicardipine.

Objective: To evaluate N-terminal pro-brain natriuretic peptide (NT-proBNP) as a marker of early pulmonary artery hypertension (PAH) and to study changes in the levels of this marker following treatment with dihydropyridine-type calcium-channel blocker (DTCCB) in patients with systemic sclerosis (SSc)., Methods: We evaluated 40 consecutive SSc patients who had been hospitalized for followup care (mean +/- SD age 56 +/- 11 years and mean +/- SD duration of cutaneous disease 9 +/- 9 years; 27 with limited cutaneous and 13 with diffuse cutaneous disease) but who had no clinical symptoms of heart failure and had a normal left ventricular ejection fraction. At baseline, 10 patients had PAH, defined as a systolic pulmonary artery pressure (sPAP) >40 mm Hg, as measured by echocardiography. Levels of NT-proBNP were determined at baseline (after discontinuation of DTCCB treatment for 72 hours), after taking 3 doses of DTCCB following treatment reinitiation (assessment 1), and after 6-9 months of continuous DTCCB treatment (assessment 2) in the 20 patients who attended regular appointments (including the 10 patients with PAH at baseline)., Results: At baseline, 13 patients had high NT-proBNP values for their ages. High NT-proBNP levels identified patients with PAH with a sensitivity of 90%, a specificity of 90.3%, a positive predictive value of 69.2%, and a negative predictive value of 96%. The NT-proBNP level correlated with the sPAP (r = 0.44; P = 0.006). By assessment 1, the number of patients with PAH and high levels of NT-proBNP had decreased from 9 of 10 to 2 of 10 (P = 0.02). This decrease was partially sustained at assessment 2 (4 of 10 patients; P = 0.06)., Conclusion: NT-proBNP is a useful biologic marker that can be used to diagnose early PAH in SSc patients without clinical heart failure. Measurement of NT-proBNP may be valuable for the evaluation of treatment with DTCCB and vasodilators in patients with PAH.